Activation of Mitogen-Activated Protein Kinases in Human Heart During Cardiopulmonary Bypass

Abstract

Abstract-Mitogen-activated protein kinases (MAPKs) have been shown to be activated in both in vitro and in vivo models of cardiac tissue in response to ischemia/reperfusion injury. We investigated whether MAPKs are activated in human heart during coronary artery bypass grafting (CABG) surgery. During elective CABG surgery of 8 patients, 3 right atrial appendage biopsies were obtained at baseline, at the end of cross-clamping, and after coronary reperfusion. The expression of the p38-MAPK, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK1/2) MAPKs was not altered during CABG. The phosphorylation and activation of both ERK1/2 and p38-MAPK were increased Ϸ2-fold by ischemia and even more (8-and 4-fold, respectively) by reperfusion. Although the ischemic period did not result in a significant activation of JNK, an Ϸ6-fold increase in JNK activity could be observed after reperfusion.In conclusion, distinct activation patterns of ERK1/2, p38, and JNK MAPKs can be observed in human heart during CABG. (Circ Res. 2000;86:1004-1007.)Key Words: myocardium Ⅲ ischemia/reperfusion Ⅲ stress-activated protein kinases T he mitogen-activated protein kinases (MAPKs) are activated by diverse stimuli and appear to mediate cellular responses including proliferation, differentiation, and adaptation to stress. 1,2 Three major subfamilies have been characterized, including the extracellular signal-regulated kinases (ERK1/2), the c-Jun N-terminal kinases (JNK1/2), and the p38-MAPKs. 2 It has been previously reported that although the ERKs are mainly involved in mediating anabolic processes such as cell division, growth, and differentiation, the JNKs and the p38-MAPKs are generally associated with cellular response to diverse stresses (reviewed in References 3 and 4).In recent years, the possible importance of MAPK activation in the heart during ischemia/anoxia and reoxygenation has been raised. 2,4 The JNKs and the p38-MAPKs have been consistently shown to be activated by myocardial ischemia/reperfusion in both animal models 4,5 and in cardiomyocyte cell lines. 6,7 The ERKs, however, have been shown to be activated in isolated animal hearts by ischemia/reperfusion by some, 5,8 although not all investigators, 4,9 possibly in response to oxidative stress. 9,10 The exact role of the MAPKs in cardiac pathophysiology in humans has not been fully elucidated, partly because of limited information regarding the activation pattern of the MAPKs in the human heart. A recent study demonstrated the expression of JNK, p38-MAPK, and ERK1/2 in the human heart. A potential clinical relevance for their action was demonstrated by an increased activity of JNK and p38-MAPK in heart failure secondary to ischemic heart disease. 11In the present study, we aimed at evaluating both the expression and activation of the different MAPKs in nonfailing human hearts by cardiopulmonary bypass during the course of coronary artery bypass grafting (CABG) surgery. Materials and MethodsThe study was performed on right atrial appendage samples ob...

Altered Expression and Activation of Mitogen-Activated Protein Kinases in Diabetic Heart During Cardioplegic Arrest and Cardiopulmonary Bypass

“…Additionally, the baseline level of phospho-p38-MAPK was increased in the uncontrolled-diabetic myocardium. The discrepancy between the findings of Talmer et al 3 and the present study also represent a pattern of oscillation between activation and deactivation of p38-MAPK pathways during CPB and reperfusion. Our results may suggest that diabetes, especially uncontrolled diabetes, plays an important role in the regulation of myocardial p38-MAPK expression and activation in the setting of CP/CPB.…”

“…3 In our present study, however, post-CP/CPB-activated-p38-MAPK was unaltered in nondiabetic and controlled-diabetic myocardium but was significantly decreased in the poorly controlled diabetic myocardium as compared with the pre-CP/CPB. Interestingly, post-CP/CPB levels of phospho-p38-MAPK were still greater in poorly controlled diabetics compared with nondiabetics and controlled diabetics.…”

“…1,2 These MAPKs are involved in several processes important in cardiac surgery, such as cytokine production, ischemia/ reperfusion, myocardial apoptosis, vascular permeability, vasomotor function, and injury. [2][3][4][5][6][7][8] Preclinical and clinical studies from our and other laboratories have demonstrated previously that alterations in the activity of p38-MAPK, ERKs, and JNKs occur as a result of cardioplegia and cardiopulmonary bypass (CP/CPB). [2][3][4][5][6][7][8] The expression and activation of MAPKs are also altered in the setting of hyperglycemia and diabetes in several animal models.…”

“…[2][3][4][5][6][7][8] Preclinical and clinical studies from our and other laboratories have demonstrated previously that alterations in the activity of p38-MAPK, ERKs, and JNKs occur as a result of cardioplegia and cardiopulmonary bypass (CP/CPB). [2][3][4][5][6][7][8] The expression and activation of MAPKs are also altered in the setting of hyperglycemia and diabetes in several animal models. [9][10][11][12][13][14] Recent studies in our laboratory demonstrated that PKC-alpha and PKC-beta are upregulated and activated in the human diabetic (type 2) myocardium in the setting of CP/CPB.…”

Activation of Protein Kinases in Chronically Hypoxic Infant Human and Rabbit Hearts

“…The clinical relevance of protein kinases in adult humans was recently demonstrated by an increased activity of JUN kinase and p38 MAPK in heart failure secondary to ischemic heart disease 3 and during cardiopulmonary bypass. 4 However, the role of PKC and MAPKs in the mechanisms by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia are unknown.…”